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Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target

DOI: 10.1073/pnas.2013620117 DOI Help

Authors: Lukasz F. Sobala (University of York) , Pearl Z. Fernandes (University of Melbourne) , Zalihe Hakki (University of Melbourne) , Andrew J. Thompson (University of York) , Jonathon D. Howe (University of Oxford) , Michelle Hill (University of Oxford) , Nicole Zitzmann (University of Oxford) , Scott Davies (University of Birmingham) , Zania Stamataki (University of Birmingham) , Terry D. Butters (University of Oxford) , Dominic S. Alonzi (University of Oxford) , Spencer J. Williams (University of Melbourne) , Gideon Davies (University of York)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 263

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 1221 , 12587 , 18598

Open Access Open Access

Abstract: Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and function. N-linked glycans are synthesized from Glc3Man9GlcNAc2 precursors that are trimmed and modified in the endoplasmic reticulum (ER) and Golgi apparatus by glycoside hydrolases and glycosyltransferases. Endo-α-1,2-mannosidase (MANEA) is the sole endo-acting glycoside hydrolase involved in N-glycan trimming and is located within the Golgi, where it allows ER-escaped glycoproteins to bypass the classical N-glycosylation trimming pathway involving ER glucosidases I and II. There is considerable interest in the use of small molecules that disrupt N-linked glycosylation as therapeutic agents for diseases such as cancer and viral infection. Here we report the structure of the catalytic domain of human MANEA and complexes with substrate-derived inhibitors, which provide insight into dynamic loop movements that occur on substrate binding. We reveal structural features of the human enzyme that explain its substrate preference and the mechanistic basis for catalysis. These structures have inspired the development of new inhibitors that disrupt host protein N-glycan processing of viral glycans and reduce the infectivity of bovine viral diarrhea and dengue viruses in cellular models. These results may contribute to efforts aimed at developing broad-spectrum antiviral agents and help provide a more in-depth understanding of the biology of mammalian glycosylation.

Journal Keywords: glycosylation; structural biology; secretory pathway; enzyme; antiviral

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography